During the earliest investigative history of the AIDS epidemic, feline immunodeficiency syndrome served as an important model in the search for a retrovirus etiology. Our recent data has shown that this model will continue to provide important insight. Feline AIDS is due to a lymphocytopathic variant of feline leukemia virus (FeLV) which will induce rapid onset, fatal immunodeficiency in 100% of viremic, genetically outbred, specific-pathogen free cats. In parallel studies we have identified molecularly cloned viruses which will consistently induce either no disease or feline AIDS, and shown that the feline AIDS virus exhibits features in common with the human AIDS virus (HIV), which, in some cases, appear to be vital to its pathogenicity, including lymphocytopathicity, marked genome instability, persistence of unintegrated DNA in infected cells, and tissue- specific replication. As with HIV, the envelope gene of the feline AIDS virus is implicated as an important determinant of pathogenicity. We propose to employ this reproducible and efficient model system in order to gain insight into the general mechanisms underlying retrovirus-induced AIDS. Our multidisciplinary approach has and will continue to emphasize in vitro and in vivo analysis of genetically engineered recombinant viruses in outbred SPF cats, in order to constantly focus on events crucial to the understanding of naturally occurring retrovirus immunodeficiency disease mechanisms in the absence of complicating intercurrent infections by other pathogens. We propose to identify the retrovirus genetic determinants responsible for induction of feline AIDS, virus cell targeting, and cytopathicity by molecular cloning and construction and testing of in vitro generated recombinant viruses to deductively locate essential regions. We also propose to investigate host response to infection by determining the humoral antibody response directed against feline AIDS viruses. Host immune response will also be evaluated as a function of viremia and disease state in order to differentiate protective and non-protective responses. Feline AIDS virus envelope protein structure will be investigated, by generation of monoclonal antibodies which might identify critically important variable regions and neutralizing epitopes, and by direct biochemical analysis.